Genetic Selection for Voluntary Alcohol Consumption in the Albino Rat.

Eriksson, K. Genetic selection for voluntary alcohol consumption in the albino rat. A n important, widely accepted experimental approach to un­ derstanding the underlying biology of diseases and their treat­ ment has been the study of animal models. However, among scientists in the alcohol research field, there was doubt even as recently as 15 years ago as to whether studying alcohol con­ sumption behavior in subhuman pri­ m a t e s a n d l o w e r a n i m a l s p e c i e s could make a major contribution to the understanding of human alcohol consumption behavior. The principal reason for this skepticism was that voluntary oral consumption of alco­ hol solutions by animals commonly available in laboratories rarely re­ s u l t e d i n s u p p ose d l y m e a ni ng f u l blood alcohol concentrations unless " unnatural " manipulations, such as limiting the animal's food intake, and behavioral conditioning procedures are used. Eriksson's seminal work, as described in this 1968 article, had a major impact in changing this view against using animal models. Since the 1950's, inbred strains of rats and mice have been observed to demonstrate different degrees of pref­ erence when they have voluntarily consumed alcohol, indicating that this t r a i t i s g e n e t i c a l l y i n f l u e n c e d. Building on this knowledge, Eriksson used selective breeding (described be­ low) to develop rat lines whose mem­ bers showed consistently high and low voluntary alcohol consumption. The procedure he employed was ele­ gant and simple. Rats were given free choice of a 10­percent (volume per volume) solution of pure alcohol in water, a plain water solution, and f o o d o v e r a 4 ­w e e k p e r i o d. R a t s showing high alcohol preference were mated to start a line (high consump­ tion line, or AA), and rats showing low alcohol preference were mated to start another line (low consumption line, or ANA). This process was re­ peated over many generations, using care to avoid mating close relatives to l e s s e n t h e d e g r e e o f i n …

A n important, widely accepted experimental approach to un derstanding the underlying biology of diseases and their treat ment has been the study of animal models. However, among scientists in the alcohol research field, there was doubt even as recently as 15 years ago as to whether studying alcohol con sumption behavior in subhuman pri m a t e s a n d l o w e r a n i m a l s p e c i e s could make a major contribution to the understanding of human alcohol consumption behavior. The principal reason for this skepticism was that voluntary oral consumption of alco hol solutions by animals commonly available in laboratories rarely re s u l t e d i n s u p p ose d l y m e a ni ng f u l blood alcohol concentrations unless "unnatural" manipulations, such as limiting the animal's food intake, and behavioral conditioning procedures are used. Eriksson's seminal work, as described in this 1968 article, had a major impact in changing this view against using animal models.
Since the 1950's, inbred strains of rats and mice have been observed to demonstrate different degrees of pref erence when they have voluntarily consumed alcohol, indicating that this t r a i t i s g e n e t i c a l l y i n f l u e n c e d . Building on this knowledge, Eriksson used selective breeding (described be low) to develop rat lines whose mem bers showed consistently high and low voluntary alcohol consumption. The procedure he employed was ele gant and simple. Rats were given free choice of a 10percent (volume per volume) solution of pure alcohol in water, a plain water solution, and f o o d o v e r a 4 w e e k p e r i o d . R a t s showing high alcohol preference were mated to start a line (high consump tion line, or AA), and rats showing low alcohol preference were mated to start another line (low consumption line, or ANA). This process was re peated over many generations, using care to avoid mating close relatives to l e s s e n t h e d e g r e e o f i n b r e e d i n g . Eventually, a stable difference be tween the AA and ANA lines of more than five to sevenfold was obtained. The continued success of Eriksson's breeding program over the years encouraged other investigators to replicate these find ings. For example, in the United States at this time, there are two pairs of high consumption and low consumption rat lines, the alcoholpreferring P and alcoholnonpreferring NP lines, and the highalcoholdrinking HAD and lowalcoholdrinking LAD lines. In Sardinia, Italy, the alcoholpreferring line is called the sP line and the nonpreferring line, the sNP line. Because the four pairs of contrasting lines were developed from parent stocks, the high consumption lines exhibit certain similarities in behavior as well as some differences. The same is true for the low consump tion lines. This is consistent with the demonstrated polygenic na ture of alcoholseeking behavior (i.e., the trait appears to be influenced by more than one gene) and supports the finding of genetic subtypes of alcoholism in humans.

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There are now hundreds of studies reporting on the behav ioral, physiological, biochemical, and genetic associations of al co h o l pr e f e r e n c e i n the se s e l e c t e d r a t li n e s . A t l e a s t tw o important associations of alcohol preference have been found in animals that have clear relevance to human alcoholconsuming behavior. One is the inverse correlation of alcohol sensitivity and preference (i.e., an animal that is highly sensitive to alcohol's ef fects will have a low preference for alcohol). Sensitivity is mea sured by the speed of recovery of impaired function after the administration of a single dose of alcohol and may be attributed to acute alcohol tolerance (i.e., the development of the ability to resist the effects of alcohol within one drinking episode). In the alcoholpreferring rats, for example, this tolerance is present even 10 days after receiving that one dose of alcohol (i.e., they will have a higher resistance to the effects of alcohol 10 days lat er when they are given another dose). These rats are therefore genetically predisposed to retaining tolerance. In humans, the work of Schuckit (1994) has shown that a lower level of re sponse or sensitivity to alcohol predicts future alcoholism.
Another area in which animal model studies have a clear rele vance to human alcohol consumption behavior is the neurobio logical basis of alcoholseeking behavior. Studies in selectively bred rats and other commonly available strains of rats have re vealed the involvement of neurotransmitters such as dopamine, serotonin, gammaaminobutyric acid (GABA), and opioids (and pathways in which these compounds are the primary neurotrans mitters) in the reinforcing actions of alcohol. Although no uni form agreement exists as to the relative importance of these pathways (this may, in fact, be attributable to the genetic differ ences between the models under study), it is worth noting that chemical compounds acting on these pathways can affect the rats' voluntary alcohol consumption. One such chemical agent is naltrexone, which has now been shown in clinical trials to be ef fective in some alcoholic patients for reducing alcohol craving. The AA and P rats played important roles in the preclinical de velopment of this treatment.
The full potential of using the selected lines of rats for study ing alcoholismrelated phenomena, pioneered by Eriksson, is still being realized. For example, with the recent report of a com plete genetic linkage map for the laboratory rat (Jacob et al. 1995), the search for the genes underlying alcoholseeking be havior can now be greatly accelerated. Furthermore, comparing the selected high consumption lines with one another and with other strains of rats under different experimental conditions pro vides a way to discern different forms of this behavioral trait and to study geneenvironment interactions. Both of these endeavors involving animal studies would be relevant for revealing genetic information that may help researchers understand more about hu man alcohol consumption behavior and alcoholism. ■ TINGKAI LI, M. D., is professor of medicine/biochemistry, School of Medicine, Indiana University, Indianapolis, Indiana.